SYCP3 Inactivates BRCA2 Increasing Risk of Genomic Instability Genome instability increases the risk for cancer. Among the diverse types of DNA damage, DNA double stranded breaks (DSBs) can drive genomic instability by their potential to induce genome rearrangements. Homologous recombination (HR) functions to accurately repair DSBs and help maintain genomic integrity. BRCA2 is a central HR protein and recruits other proteins such as RAD51 in somatic cells and RAD51 and DMC1 in germline cells to participate in the two signature steps of HR: 1) Homology search and 2) DNA strand invasion. Loss of BRCA2 function is associated with increased risk of breast, ovarian and other cancers. Mechanisms that inactivate BRCA2 function other than loss of heterozygosity are yet to be determined. My research addresses this gap in knowledge and defines a new mechanism by which misexpression of the germline protein SYCP3 in somatic cells inhibits BRCA2-mediated HR. SYCP3 is an essential structural component of the meiosis-specific synaptonemal complex and is required for proper recombination and chromosome segregation during meiosis. SYCP3 is typically expressed only in germline cells (e.g., in testis, ovary) but not in somatic cells. Emerging evidence indicates that SYCP3 is misexpressed in certain cancer cells and primary tumors, and hence SYCP3 has been termed a cancer/testis antigen. The role of SYCP3 in meiosis is relatively well understood but not much is known about its potential effects in somatic cells. In germline cells, both SYCP3 and BRCA2 are present and they function together for normal HR-mediated repair of meiotic DSBs, but SYCP3 expression in somatic cells results in a DNA repair defect. Recently, it was reported that in somatic cells SYCP3 interacts with BRCA2 and impairs recruitment of RAD51 involving mechanisms that remain to be defined. My working model is that: (1) In germline cells, SYCP3 promotes the interaction of BRCA2 and DMC1 and thereby enables HR; (2) In somatic cells, SYCP3 limits the interaction of BRCA2 and RAD51 and thereby disrupts HR. My hypothesis is that SYCP3 regulates the differential interaction of BRCA2 with RAD51 and DMC1. Specific Aim 1 will establish the biochemical mechanism by which SYCP3 leads to functional loss of BRCA2 in somatic cells by in vitro assays using purified proteins. Specific Aim 2 will use cell based models to determine the biological significance of the interaction between SYCP3 and BRCA2 on HR efficiency and response to genotoxic stress. The findings from this proposal will determine the mechanism by which SYCP3 misexpression in somatic cells leads to BRCA2 functional deficiency. The findings will establish SYCP3 expression in tumors as a potential biomarker for HR deficiency, which will also enable patients for cancer therapeutics like Poly (ADP-ribose) polymerase inhibitors.